From Contaminant Molecules to Cellular Response: System Quantification and Predictive Model Development

Project Overview:

The network aims at understanding cellular responses to chemical stressors with a systems perspective, which involves intra-cellular transport of the chemical, reaction with sub-cellular target sites and the cell’s response at the transcriptional and post-transcriptional level. The hypothesis underlying this network is that the complexity of signalling pathways neither solely resides in the number of components and interactions involved, nor exclusively in their associated structural and physico-chemical properties. Instead, it also resides in the hierarchical connection across space and time scales ranging from single molecules to the cellular level.

We propose to explore this hypothesis by coupling systematic large-scale cell-based experiments with the integrated simulation of the intracellular transport and regulatory networks. We selected the polycyclic aromatic hydrocarbon (PAH), benzo(a)pyrene (BaP), as the model chemical to initiate this research. The uptake and sub-cellular partitioning of BaP as well as BaP interaction with the aryl hydrocarbon receptor(AhR) signalling pathway and resulting changes on genome and proteome level will be under investigation. The AhR signalling pathway is a central route for the toxic effects of many organic chemicals including, beside PAHs, dioxins, furans and biphenyls. Therefore, results obtained from this model might help to unravel the effects of other toxic agents as well.

Highly resolved experimental data on the spatial and temporal distribution of BaP molecules in all major cellular compartments and on the interaction of BaP with the AhR pathway will be generated. In particular, the effective number of receptor-ligand complexes in the cell nucleus is in the focus and considered as a prerequisite for succeeding gene expression and protein synthesis. Genome and proteome analysis will subsequently be carried out. Data-validated computational models explaining movement of BaP within the cell and BaP-AhR interaction as well as prediction models for dose- and time-dependent induction of gene and protein expression in response to activation via the AhR signalling pathway will be developed. An integrated model for the entire signalling pathway from extracellular exposure of the cell with BaP to cell response will be the final aim of this network.

The data and the models developed in this study will provide new insights into the systemic regulation of the AhR pathway and the study will serve as a prototype for elucidating other stress response pathways in the future.

Network Coordinators:

Dr. Irina Lehmann, UFZ Leipzig

Prof. Dr. Sabine Atttinger, UFZ Leipzig (Deputy Coordinator)

Further Project Leaders:

Kristin Schirmer, UFZ Leipzig

Martin von Bergen, UFZ Leipzig

Thomas Hanke, Dresden Univ. of Technology

Andreas Beyer, University of California San Diego / Dresden Univ. of Technology